Homologous desensitization of the A1-adenosine receptor system in the guinea pig atrioventricular node

The objective of this study was to determine whether chronic infusion (7 days) of an A1-adenosine receptor (A1-AdoR) agonist, R-N6-phenylisopropyladenosine (R-PIA), causes homologous and/or heterologous desensitization of the atrioventricular (AV) nodal A1-AdoR system in the guinea pig. The negative dromotropic effects of adenosine, the A1-AdoR agonist N6-cyclopentyladenosine and the muscarinic cholinergic agonist carbachol on hearts from control and treated animals were compared. The potencies of adenosine and N6-cyclopentyladenosine to prolong AV nodal conduction time of hearts from treated animals were significantly reduced compared with control. In contrast, no difference in the potency of carbachol to prolong AV nodal conduction time in the hearts from control and R-PIA-treated guinea pigs was found. The densities of A1-AdoRs in atria and ventricles of treated hearts were 54% (P < .05) and 36% (P < .05) lower than in control hearts, respectively. The number of A1-AdoRs with high affinity for agonists was 37% lower (P < .05) in ventricular membranes prepared from hearts of R-PIA-treated guinea pigs than in membranes from control hearts. In contrast, atrial or ventricular muscarinic acetylcholine receptor densities were not different in hearts of control compared with hearts of treated animals. An up-regulation of the density of nucleoside transporter sites was observed in hearts of treated animals. The quantities of Gi and G(o) in atrial membranes prepared from hearts of treated guinea pigs were lower by 46% and 80%, respectively, than the quantities of Gi and G(o) in atrial membranes prepared from hearts of control animals. It was concluded that chronic administration of R-PIA to guinea pigs desensitized the AV node to the negative dromotropic effect of adenosine in a homologous but not a heterologous manner and desensitization of the AV node response to adenosine was associated with down-regulation of A1-Ado receptors, a decrease in the fraction of A1-Ado receptors in the high-affinity state and a decrease in the contents of Gi and G(o) proteins.